One signaling pathway which data suggests may be involved in the adverse consequences of diabetes and hypertension is the JAK/STAT pathway. Our data support the idea that activation of this pathway is critical to the ability of ANGII to cause h3T)ertension in the models of ANG Il-high salt and high dose ANG II (normal salt). Preliminary data further suggest JAK2 appears to play a critical role in the molecular mechanisms utilized by ANG II to cause vascular contraction. These studies suggest that an alteration in the inhibitor of JAK2 activity, SHP-1, may be involved in the activation of JAK2 observed. Furthermore, in vivo, Norepinephrine also activates JAK2 during hypertension suggesting that JAK2 may be a common agent for the increase in blood pressure. Therefore, we propose to test the hypothesis that activation of the JAK/STAT pathway in vivo during hypertension contributes to the development of vascular endothelial dysfunction and renal complications as assessed by alterations in glomerular filtrate rate (GFR), renal blood flow and the development of glomerular sclerosis. The goal of these proposed studies is to use an integrative approach combining whole animal physiology with a biochemical analysis of the intracellular signaling mechanisms to elucidate the molecular mechanisms involved in the development of complications. To achieve this goal we are proposing three specific aims. Specific Aim 1: Determine if the same members of the JAK/STAT pathway are activated in the DOCA-salt, ANG Il-high salt and NE-lnfiised models of hypertension. Specific Aim 2: Determine the effects of hypertension on the role of the cytosolic protein tyrosine phosphatases, SHP-1, SHP-2 and PTP-IB, and suppressors of c3rtokine signaling (SOCS) that regulate the JAK/STAT pathway. Specific Aim 3: Determine the interaction of the JAK/STAT with other signaling pathways already implicated in hypertension, specifically PKC, PKA, Rho-kinase and PI3- kinase. Understanding the molecular changes that contribute to the development of end-organ damage in disease states is critical to create additional clinical interventions that could be used in conjunction wnth traditional therapy.